In recent years, regulators have often called attention to the trend of pharmaceutical products and their respective active ingredients being manufactured abroad, making it more difficult and expensive for FDA officials to ensure product quality and integrity as they enter the US. One oft-cited statistic by FDA is that 40% of finished pharmaceutical products are imported and 80% of all active pharmaceutical ingredients are imported.
Compounding FDA’s inspection difficulties is the increased use of the Internet by consumers to order products based on price, which places downward pricing pressure on manufacturers, some of which cut corners on product quality in order to gain a price edge over their competitors. The problem is now prominent enough to have raised discussion within FDA about promoting the use of a manufacturing “scorecard” to promote consumer awareness of quality.
Whatever the challenges, legislators and regulators seemed to agree on at least one solution: more facility inspections by FDA officials. As a first step, Section VII of FDASIA required all foreign drug and device facilities, including those manufacturing active pharmaceutical ingredients, exporting their products to the US to register with FDA. It also called for more frequent inspections of foreign facilities by FDA, as well as new risk-based inspection methodologies and partnerships with foreign regulatory authorities.
“These authorities increase FDA’s ability to collect and analyze data to make risk-informed decisions, employ risk-based approaches to facility oversight, partner with foreign regulatory authorities to leverage resources through information sharing and recognition of foreign inspections, and drive safety and quality throughout the supply chain,” FDA wrote in a Federal Register posting on Section VII.
But, as FDA adds later in the same Register notice, the law leaves open a huge number of questions that FDA still must answer, and the agency is now turning to industry to help it to obtain answers to some of them. “Implementation of Title VII of FDASIA is difficult and complex, and requires not only the development of new regulations, guidances, and reports, but also major changes in FDA information systems, processes, and policies,” it wrote. Regulators bring up the example of Section 713, which calls for FDA to obtain information from importers. “Such information may include: Information demonstrating the regulatory status of the drug, such as the new drug application number, abbreviated new drug application number, investigational new drug number, or drug master file number; facility information, such as proof of registration and the unique facility identifier; indication of compliance with current good manufacturing practice (CGMP), testing results, certifications relating to satisfactory inspections, and compliance with the country of export regulations; and any other information deemed necessary and appropriate by the Secretary to assess compliance.”
It’s the last of these criteria – “any other information deemed necessary and appropriate” – that has FDA most seeking input from industry. Is there any other information that would (or would not) be useful for regulators to consider when assessing a product? Should there be different requirements for different types of importers, products or trusted providers? In addition, FDA said it is now consulting with the US Department of Homeland Security and the US Customs and Border Protection agency to come up with a unique facility identifier system for registering commercial importers, and will issue regulations establishing good importer practices within the next two years.
FDA also said it will entertain answers regarding how to assess imported products for adherence to current good manufacturing practice (CGMP) regulations. “What information could importers submit at the time of entry to demonstrate that a drug offered for import complies with U.S. CGMP requirements,” FDA asked. That could, in theory, bring FDA closer to the EU own API requirements, which require the importer to have written assurances of CGMP quality, both from the company and a local trusted regulator.
Questions for Industry
FDA’s announced it will be holding a meeting on 12 July 2013 at its Silver Spring, Maryland campus, at which time it will solicit answers to the following questions:
A. Section 713: Standards for Admission of Imported Drugs
- How should the regulations implementing section 801(r) of the FD Act (21 U.S.C. 381(r)), as amended by section 713 of FDASIA, define “importer” as that term is used in 801(r)(l)?
- What information should FDA require importers to submit at the time of entry that would demonstrate a drug’s compliance with applicable requirements of the FD&C Act as a condition of granting admission of the drug into the United States?
- What information could an importer submit to FDA at the time of entry to demonstrate compliance with applicable requirements of the FD&C Act relating to:
- homeopathic drugs intended for human use,
- articles intended for human drug compounding,
- articles intended for animal drug compounding, and
- drugs intended for research?
- What facility information should FDA request from importers at the time of entry to help assess whether a drugcomplies with applicable requirements of the FD&C Act?
- What information could importers submit at the time of entry to demonstrate compliance with country of export regulations in accordance with section 801(r)(2)(C) of the FD&C Act?
- What information could importers submit at the time of entry to demonstrate that a drug offered for import complies with U.S. CGMP requirements?
- What information could importers submit at the time of entry that would serve as evidence of satisfactory inspection, such as by a foreign government or an agency of a foreign government?
- Should FDA require that importers submit certificates of analysis (COAs) to the Agency as a condition of admission under section 801(r) of the FD&C Act? If so, how could an importer demonstrate a COA’s authenticity?
- Section 801(r)(4)(B)(i) of the FD&C Act permits FDA, as appropriate, to consider differences among imports and types of drugs and “based on the level of risk posed by the imported drug, provide for expedited clearance for those importers that volunteer to participate in partnership programs for highly compliant companies and pass a review of internal controls, including sourcing of foreign manufacturing inputs, and plant inspections.”
- What criteria should FDA use to evaluate potential participants in “voluntary partnership programs for highly compliant companies”?
- How could FDA take into account differences among importers and types of drugs to allow for expedited entry as part of a voluntary partnership program?
- What risk factors should FDA consider when determining drug admissibility under a voluntary partnership program?
- What benefits and burdens may be created by requiring drug importers to electronically submit information demonstrating that a drug complies with applicable requirements of the FD&C Act as a condition of admission? How could we minimize any possible burdens? How do we strike a reasonable balance between rigor and efficiency in requiring information that is both reliable and yet can be submitted and reviewed efficiently?
B. Section 714: Registration of Commercial Importers of Drugs
- How should the regulations implementing section 714 of FDASIA (section 801(s) of the FD&C Act) define “commercial importer” to ensure that the appropriate entities are required to register with FDA and meet requirements regarding good importer practices (GIP)? Should these “commercial importers” be the same entities as the “importers” required to comply with the standards for admission to be adopted under section 801(r) of the FD&C Act?
- Under section 801(s)(1) of the FD Act, the registration regulations will apply to commercial importers of “drugs.” A “drug” is defined in section 201(g)(1) of the FD Act (21 U.S.C. 321(g)(1)) and includes, but is not limited to, finished dosage form drug products, drugs for further processing, active pharmaceutical ingredients, and other drug components, including inactive ingredients. Should commercial importers of certain types of drugs, such as inactive ingredients, be exempt from the commercial importer registration requirements? Should the importation of drugs for certain purposes (e.g., research use) be exempt from registration?
- What information should commercial importers be required to submit as part of their registration?
- What benefits and burdens might be created by requiring commercial drug importers to register with FDA? How can we minimize any possible burdens (e.g., through gradual implementation, exemption of certain commercial importers, use of other alternatives)?
C. Section 714: Good Importer Practices
- How might FDA structure the GIP regulations to avoid imposing redundant regulatory requirements on commercial importers that also are drug manufacturers and therefore would be subject to both the GIP and CGMP requirements?
- Should the GIP regulations require commercial importers of drugs to establish drug safety management programs to ensure that imported drugs meet the requirements of the FD&C Act and the Public Health Service Act, as applicable? If so, what matters (e.g., procedures, personnel) should the GIP regulations require commercial importers to address in such programs?
- What drug safety management programs or other measures do commercial importers currently have in place to ensure that imported drugs are manufactured in compliance with applicable FDA requirements? How do these programs and measures differ for different “types” of drugs?
- Should the GIP regulations include qualifications and training for personnel who perform GIP activities? If so, what qualifications and training should be required?
- Should the GIP regulations include a requirement for commercial importers to assess whether it is appropriate to import a particular drug from a particular foreign supplier? If so, what information on the drug and the supplier should the commercial importer be required to consider as part of this assessment?
- Should commercial importers be required to conduct activities to verify that a drug that is offered for import is in compliance with applicable U.S. requirements (e.g., the CGMP regulations) and are not adulterated under section 501 of the FD Act (21 U.S.C. 351) or misbranded under section 502 of the FD Act? If so, what supplier verification activities should commercial importers be required to conduct?
- Should there be different supplier verification or other GIP requirements for different “types” of drugs? Should there be different requirements for particular types of finished dosage form drug products that might be associated with different levels of risk (e.g., sterile injectables, drugs that require temperature controls)? If so, what should these requirements be?
- Should the GIP regulations require commercial importers to obtain a COA for each imported drug? Should such a requirement apply only to certain types of drugs or commercial importers? If commercial importers are required to obtain COAs, should the commercial importer also be required to conduct testing to verify the accuracy of the COA?
- Should the GIP regulations include specific requirements for drugs imported for export in accordance with section 801(d)(3) of the FD&C Act? If so, what should these requirements be?
- How should the GIP regulations reflect or incorporate the requirements concerning the standards for admission of imported drugs under section 801(r) of the FD&C Act? For example, should the GIP requirements include the adoption of procedures to ensure that the commercial importer submits the compliance information required under section 801(r) and the regulations implementing that section? If so, what procedures should commercial importers be required to follow to ensure that these requirements are met?
- Should the GIP regulations require commercial importers to take corrective actions when the drugs they import or offer for import are not in compliance with applicable U.S. requirements? If so, what actions should importers be required to take?
- Should the GIP regulations include a requirement for commercial importers to list the drugs they import or offer for import? If so, what information should be required with listing?
- What records should commercial importers be required to maintain under the GIP regulations?
- What other matters, if any, should the GIP regulations address?
- How should FDA take into account “differences among importers and types of imports, including based on the level of risk posed by the imported product,” in determining reasonable time periods for commercial importers to come into compliance with the GIP regulations under section 714(d)(3) of FDASIA? In considering such differences, how should FDA determine the level of risk posed by an imported drug?
- What benefits and burdens might be created by requiring commercial importers to comply with GIP regulations? How can we minimize any possible burdens (e.g., through gradual implementation, exemption of certain commercial importers, use of other alternatives)?
REFERENCE: Alexander Gaffney, RF News Editor; 19 JUN 2013; RF Regulatory Focus